For some decades, it has become evident that dyslipidemias are a major risk factor for the occurrence of cardiovascular diseases. Epidemiological studies carried out on human subjects made evident that a high level of LDL-C (low-density lipoprotein cholesterol) associated to a reduced level of HDL-C (high-density lipoprotein cholesterol) induce early atherosclerosis. On the other hand, several studies showed that the risk of coronary heart disease (CHD) can be reduced through hypocholesterolemic therapy. Framigham Heart Study, Multiple Risk Factor Intervention (MRFIT) and Lipid Research Clinics (LRC) found a direct relation between the serum concentration of LDL-C and the event rates in patients (male and female) with acute coronary without CHD history. Many studies showed that the risk of coronary diseases can be reduced due to hypolipemiant therapy. Until 1987, therapeutic strategies directed to lipid reduction were essentially limited to a diet poor in saturated fats and bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), fibrates and probucol. Unfortunately, all these treatments have limited efficacy or tolerability, or both. Only after the appearance of HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, derivates and analogous thereof, medicals were able to obtain comparatively high reductions of cholesterol in plasma with very few adverse effects.
The administration of these compounds is associated to a reduction of mortality rate associated to coronary heart disease, and the risk of acute myocardial infarction, coronary revascularization procedures, cerebrovascular accident and peripheric vascular disease. The most frequently reported adverse effects are of muscular (myopathy) and hepatic (increase of hepatic enzymes) nature.
The HMG-CoA reductase inhibitors are indicated for dyslipidemia patients, essentially with LDL-C increase, when diet turns out to be insufficient for controlling the disorder. Patients with additional risk factors, like coronary heart disease or equivalents, diabetes mellitus and risk factors for coronary heart disease must be treated timely and intensively. In these circumstances, the object to be attained for LDL-C serum concentration (<100 mg/dl) requires higher doses of HMG-CoA inhibitors and/or association with other compounds.
This therapeutic area has been object of intense investigation and novel hypolipemiant agents are being studied.
The present invention discloses novel compounds useful for the treatment of hypocholesterolemia and atherosclerosis, a preparation process thereof and pharmaceutical compositions containing them.
The preparation of inorganic esters through the attack of an inorganic acid to an alcohol is known for a long time (see e.g. “Advanced Organic Chemistry, Reaction Mechanisms and Structure” 4th edition, Jerry March, Wiley Interscience 1992). Namely, this reaction is used for the industrial production of detergents and cleaning agents, when fatty alcohols are made to react with sulphuric acid and subsequently converted into salts. However, these compounds are structurally different from the compounds of the present invention. In the prior state of art, no reference to general formula I was found, neither to processes for their preparation, or attempts for their synthesis and, as a result, no reference to possible industrial applications was found. The reaction using as substrate d-1-gluconic acid, or the racemic mixture, salts or lactones thereof for providing the corresponding monosulfates is new.